Growing Arteries: Science Fiction or Reality?

Atherosclerosis, or hardening of the arteries, is a major health problem and is the number one cause of death and major illness in the Western World. Until recently, the medical field focused most of its attention on blockages in the heart arteries—a disease known as coronary artery disease. However, atherosclerosis does not affect just the heart arteries; it affects all arteries in the body. Collectively, these blockages cause major problems including strokes, kidney problems, and circulation problems in the leg. The latter is commonly known as peripheral arterial disease (PAD).

PAD is now recognized to be a very common disease and has been shown to affect up to 27% of the elderly and those in high-risk groups (smokers and diabetics). Unfortunately, the majority of people with PAD do not have symptoms. For those who do experience symptoms, the first and most common is intermittent claudication, a pain or aching in the leg or calf that occurs with walking and goes away with resting. When PAD becomes severe, it is called critical limb ischemia (CLI). Persons with CLI have pain in their leg without any activity, for example, when resting at night. The legs are often discolored, and they can develop ulcers that cannot heal. These patients are at very high risk of amputation and death from heart disease. (See Keeping in Circulation, Vol.4, No. 2, for more information on CLI.)

Despite the fact that PAD is almost as common as coronary artery disease, treatment options for patients with PAD are quite limited. Most of our therapies for PAD are designed to limit so-called risk factors for atherosclerosis. Patients are encouraged to stop smoking, have high blood pressure treated, control diabetes, start a diet, and use medications to control cholesterol. Although these therapies have positive effects on atherosclerosis, they do not correct the underlying problem of PAD, which is the inability to improve blood flow to the legs. In contrast, for patients with coronary disease, physicians have a large number of therapies that are able to modify and improve blood flow to the heart.

Angiogenesis is the growth of blood vessels that are already present in the adult body. The concept that scientists could grow blood vessels in such a way as to improve blood flow to a target organ such as the leg is a process known as therapeutic angiogenesis. In most situations, the investigation method known as therapeutic angiogenesis involves the delivery of proteins or genes that are designed to make selected proteins permit the growth of blood vessels. The most widely studied of these proteins are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Over the past 20 years, a large number of studies have been done in animal models of human disease. These have demonstrated the possibility that these or related agents may be of help in humans. Space permits a short review of only the major studies that have been conducted in the area of therapeutic angiogenesis for intermittent claudication, which is one of the major symptoms of PAD.

The TRAFFIC study enrolled 190 patients with severe intermittent claudication. These patients, on average, were as sick as patients with advanced heart failure, and many of the patients had undergone unsuccessful attempts at surgical and catheter-based (angioplasty) treatments designed to improve blood flow to their legs. The patients were randomized (which means that each one had an equal chance of being placed in any one of the groups) into three groups with three different types of treatment: two intra-arterial doses of a placebo (a treatment using a "sugar pill" without real medicine), one intra-arterial dose of bFGF followed by a placebo 30 days later, or two intra-arterial doses of bFGF at baseline at days 1 and 30. The major finding of the study was that bFGF was able to improve walking time in these patients. This treatment resulted in a small but significant increase in the blood pressure in the leg, compared to the blood pressure in the arm, which further suggests that therapeutic angiogenesis in humans is a sound concept.

Not all of these studies have been positive. The RAVE trial studied patients with intermittent claudication which was present only in the calves of the legs. This is really present in only 10% of all patients with intermittent claudication. The study showed that, although all patients in the trial got better, there was no difference in the improvement between those who received the active medicine and those who received the placebo. Another study recently presented at a recent American Heart Association meeting was also disappointing since the medicine did not result in a significant increase in exercise time over the placebo. However, all of these studies help us to understand how to test these medicines. Future studies are planned in attempts to see how the medicines work.

Studies are also being conducted in PAD in the area of critical limb ischemia. Patients suffering from CLI are in desperate need for therapies. The earliest studies were conducted in Boston, Massachusetts, by the late Dr. Jeffery Isner. Over several years, a large number of patients with CLI were treated in open label manner (which means that everyone knew that he or she was receiving the real medicine) with very encouraging early results. Another angiogenesis agent, acidic FGF, is being used in clinical trials in the U. S., and some early results have been published. While encouraging, more studies are needed and are under way to evaluate this approach. Currently, in the U.S., there are several ongoing trials using medicines compared with placebos in patients with CLI including one trial that uses acidic FGF (Gencell) and the another that uses Hepatocyte Growth Factor (AnGes Mg). Data from these trials are expected to be available in 2005.

The field of angiogenesis is moving in a number of different directions. While many of the studies like those described above included the use of a single protein at a single time point, newer and more aggressive approaches are being taken. Approaches that have the ability to change the levels of many different proteins at the same time are under way. One example is the hypoxia-inducible factor 1, which is made and used by the body to help tissue respond to the lack of oxygen. Hepatocyte growth factor is also an angiogenesis protein that may have a number of different effects. Finally, studies are underway using cells from a patient's own body, given back into the leg to try to limit the amount and extent that blood flow to the leg is decreased.

The concepts that the body can build blood vessels around blockages and that the body has the ability to produce therapeutic angiogenesis have been recognized for a long time. Therapeutic angiogenesis tries to reproduce what we know the body is able to do in some cases. Encouraging data from some trials are now available. The approaches to the studies are getting better. Importantly, patients who are enrolled in clinical trials receive excellent medical care and, in many cases, they improve as part of their participation in the study. Finally, it is clear that poor blood flow is the problem in PAD and therapeutic angiogenesis, while still under study, may have the ability to improve blood flow and help patients with PAD.

About the Author: Brian H. Annex, MD, is an Associate Professor of Medicine at Duke University Medical Center and Director of the Therapeutic Angiogenesis Research Program. He works at Duke University and the Durham VA Medical Center. Dr. Annex has published more than 60 manuscripts, 9 editors, and 9 book chapters. Dr. Annex has research support from the NIH, AHA, and the VA Medical System.